The present invention relates to metalloproteinase inhibitors and, more particularly, relates to novel compounds, compositions and methods for prophylaxis and treatment of inflammation, tissue degradation and the like. This invention, in particular, relates to novel azepine and larger medium ring compounds, compositions containing such compounds and methods of use of such compounds. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Metalloproteinase enzymes, such as collagenases, stromelysins, gelatinases and TNF convertase, may contribute to the onset or etiology of, or exacerbate disease states which are related to, connective tissue degradation, secretion of proinflammatory cytokines and the like. For example, matrix metalloproteinases, such as collagenases, stromelysins and gelatinases, are thought to be involved in the tissue breakdown observed in rheumatoid arthritis; osteoarthritis; osteopenias (e.g., osteoporosis); periodontitis; gingivitis; corneal, epidermal and gastric ulceration; and tumour metastasis, invasion and growth; in neuroinflammatory disorders, such as myelin degradation (e.g., multiple sclerosis); and in angiogenesis dependent diseases, such as arthritic conditions; cancer; solid tumor growth; psoriasis; proliferative retinopathies; neovascular glaucoma; ocular tumours; angiofibromas; hemangiomas; nephritis; pulmonary inflammation; and restenosis.
Tumor Necrosis Factor alpha (TNF-.alpha.) is a proinflammatory cytokine secreted by a variety of cells including monocytes and macrophages in response to many inflammatory stimuli (e.g., lipopolysaccharide--LPS) or external cellular stress (e.g., osmotic shock, peroxide). Elevated levels of TNF play a major role in mediating many inflammatory disease states. Elevated levels of TNF-.alpha. may contribute to the onset, etiology, or exacerbate the following disease states: rheumatoid arthritis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; antiviral therapy including those viruses sensitive to TNF-.alpha. inhibition--HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, and the herpes viruses including HSV-1, HSV-2, and herpes zoster; muscle degeneration; cachexia; Reiter's syndrome; type II diabetes; bone resorption diseases; graft vs. host reaction; ischemia reperfusion injury; atherosclerosis; brain trauma; Alzheimer's disease; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; and fever and mylagias due to infection.
Several approaches have been taken to block the effects of TNF-.alpha.. One approach involves utilizing soluble receptors for TNF-.alpha. (e.g., TNFR-55 or TNFR-75) which have demonstrated efficacy in animal models of TNF-.alpha. mediated disease states. A second approach to neutralizing TNF-.alpha. utilizing a monoclonal antibody specific to TNF-.alpha., cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al., Immunological Reviews p.195-223 (1995)).
The above approaches block the effects of TNF-.alpha. by either protein sequesterization or receptor antagonism, but an additional approach to blockade is to intervene in the cellular secretion of TNF. TNF convertase is thought to be a metalloproteinase enzyme involved in the cellular secretion of TNF-.alpha. (Mohler et al., Nature 370:218-220, 1994; Gearing et al., Nature 370:555-557, 1994; McGeehan et al., Nature 370:558-561, 1994). Inhibition of TNF convertase is thought to be an additional approach to intervene in the cellular secretion of TNF-.alpha.. For example, a metalloproteinase inhibitor was shown to inhibit cellular secretion of TNF-.alpha., in vitro and in vivo, which was thought to be due to inhibition of TNF convertase (McGeehan et al., Nature 370:558-561, 1994). While evidence as to the nature of intervention by metalloproteinase inhibitors in the cellular secretion of TNF-.alpha. exists, additional or alternative mechanisms of action by which such compounds inhibit TNF secretion may be involved, such as by intervening at a point on the pathway between extracellular stimulus and secretion of protein.
Since TNF-.alpha. is upstream in the cytokine cascade of inflammation wherein elevated levels of TNF-.alpha. lead to elevated levels of other cytokines including IL-1, IL-6 and IL-8, inhibiting the secretion of TNF-.alpha. may also reduce levels of other cytokines including but not limited to IL-1, IL-6 or IL-8.
Further, TNF-.alpha. is thought to play a role in head trauma, stroke and ischemia. For instance, in animal models of head trauma (rat), TNF-.alpha. levels increased in the contused hemisphere (Shohami et al., J. Cereb. Blood Flow Metab. 14:615-619 (1994)). In a model of ischemia wherein the middle cerebral artery was occluded in rats, the levels of mRNA of TNF-.alpha. increased (Feurstein et al., Neurosci. Lett. 164:125-128 (1993)). Administration of TNF-.alpha. into the rat cortex resulted in significant PMN accumulation in capillaries and adherance in small blood vessels. The TNF-.alpha. promotes the infiltration of other cytokines (IL-1b, IL-6) and also chemokines, which promote neutrophil infiltration into the infarct area (Feurstein Stroke 25:1481-1488 (1994)).
TNF-.alpha. also may play a role in promoting certain viral life cycles and disease states associated with them. For instance, TNF-.alpha. secreted by monocytes induced elevated levels of HIV expression in a chronically infected T cell clone (Clouse et al., J. Immunol. 142:431 (1989)). The role of TNF-.alpha. in the HIV associated states of cachexia and muscle degradation has been discussed (Lahdevirta et al., The American J. Med. 85:289 (1988)).
WO 96/33172 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted 6 membered ring heterocycle hydroxamic acid derivatives, such as N-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds, and their preparation and use as inhibitors of matrix metalloproteinases and TNF production.
EP 606046 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted 5-6 membered ring heterocycle hydroxamic acid derivatives, such as N-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds and N-arylsulfonyl- and N-heteroarylsulfonyl-1,2,3,4-tetrahydroisoquinolinyl-2-hydroxamic acid compounds, preparation and use as inhibitors of matrix metalloproteinases.
WO 97/18194 discloses certain cyclic and heterocyclic N-substituted .alpha.-substituted iminohydroxamic and carboxylic acids, and their preparation and use as inhibitors of matrix metalloproteinases.
EP 803505 discloses optionally substituted aryl fused N-heterocycles and their preparation and use as inhibitors of metalloproteinases.